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PubMed2005

Ionic mechanisms of histamine-induced responses in guinea pig intracardiac neurons.

Histamine, released from mast cells, can modulate the activity of intrinsic neurons in the guinea pig cardiac plexus. The present study examined the ionic mechanisms underlying the histamine-induced responses in these cells. Histamine evokes a small membrane depolarization and an increase in neuronal excitability. Using intracellular voltage recording from individual intracardiac neurons, we were able to demonstrate that removal of extracellular sodium reduced the membrane depolarization, whereas inhibition of K+ channels by 1 mM Ba2+, 2 mM Cs+, or 5 mM tetraethylammonium had no effect. The depolarization was also not inhibited by either 10 microM Gd3+ or a reduced Cl- solution. The histamine-induced increase in excitability was unaffected by K+ channel inhibitors; however, it was reduced by either blockage of voltage-gated Ca2+ channels with 200 microM Cd2+ or replacement of extracellular Ca2+ with Mg2+. Conversely, alterations in intracellular calcium with thapsigargin or caffeine did not inhibit the histamine-induced effects. However, in cells treated with both thapsigargin and caffeine to deplete internal calcium stores, the histamine-induced increase in excitability was decreased. Treatment with the phospholipase C inhibitor U73122 also prevented both the depolarization and the increase in excitability. From these data, we conclude that histamine, via activation of H1 receptors, activates phospholipase C, which results in 1) the opening of a nonspecific cation channel, such as a transient receptor potential channel 4 or 5; and 2) in combination with either the influx of Ca2+ through voltage-gated channels or the release of internal calcium stores leads to an increase in excitability.

Animals↗
PubMed2003

Expression level of the canonical transient receptor potential 3 (TRPC3) channel determines its mechanism of activation.

Studies on the mechanism of activation of canonical transient receptor potential (TRPC) channels have often yielded conflicting results. In the current study, we have investigated the influence of expression level on the mode of regulation of TRPC3 channels. At relatively low levels of expression in DT40 chicken B-lymphocytes, TRPC3 was activated by the depletion of Ca2+ stores. Expression was increased by either transfecting with a 10-fold greater concentration of plasmid or transfecting with TRPC3 under control of a more efficient avian beta-actin promoter. At higher levels of expression, TRPC3 was no longer store-operated but could be activated through receptor-coupled phospholipase C. Under these expression conditions, TRPC3 was efficiently activated in DT40 cells lacking inositol 1,4,5-trisphosphate receptors. The Ca2+ store-operated channels formed upon expression of TRPC3 at limited levels were blocked by gadolinium; the receptor-activated channels formed upon expression of higher levels of TRPC3 were insensitive to gadolinium. These findings indicate that a single ion channel protein can form or contribute to the formation of channels regulated in two very distinct ways, i.e. either by phospholipase C-derived messengers or Ca2+ store-depletion. The mechanism of regulation of the channels depends on their level of expression.

Animals↗
PubMed2007

TRP channels and kidney disease: lessons from polycystic kidney disease.

Important insights in to the function of members of the TRP (transient receptor potential) channel superfamily have been gained from the identification of disease-related mutations. In particular the identification of mutations in the PKD2 gene in autosomal dominant polycystic kidney disease has revealed a link between TRP channel function, mechanosensation and the role of the primary cilium in renal cyst formation. The PKD2 gene encodes TRPP2 (transient receptor potential polycystin 2) that has significant homology to voltage-activated calcium and sodium TRP channels. It interacts with polycystin-1 to form a large membrane-associated complex that is localized to the renal primary cilium. Functional characterization of this polycystin complex reveals that it can respond to mechanical stimuli such as flow, resulting in influx of extracellular calcium and release of calcium from intracellular stores. TRPP2 is expressed in the endoplasmic reticulum/sarcoplasmic reticulum where it also regulates intracellular calcium signalling. Therefore TRPP2 modulates many cellular processes via intracellular calcium-dependent signalling pathways.

Amino Acid Sequence↗
PubMed2006

Structure-function relationship of the TRP channel superfamily.

Transient receptor potential (TRP) channels are involved in the perception of a wide range of physical and chemical stimuli, including temperature and osmolarity changes, light, pain, touch, taste and pheromones, and in the initiation of cellular responses thereupon. Since the last decade, rapid progress has been made in the identification and characterization of new members of the TRP superfamily. They constitute a large superfamily of cation channels that are expressed in almost all cell types in both invertebrates and vertebrates. This review summarizes and discusses the current knowledge on the TRP protein structure and its impact on the regulation of the channel function.

Animals↗
PubMed2001

Receptor-operated osteoclast calcium sensing.

Osteoclasts "sense" elevated extracellular calcium, which leads to cytoskeletal changes that may be linked to phospholipase C (PLC) activation and the associated rise in intracellular calcium ([Ca(2+)](i)). Since PLC is linked to transient receptor potential channels (trp), we hypothesized that receptor activated calcium influx due to this channel type would be activated by osteoclasts sensing [Ca(2+)](e). We found that high [Ca(2+)](e) induced similar intracellular Ca(2+) rises in chicken osteoclasts with or without intracellular Ca(2+) store depletion by either TPEN or thapsigargin, thus defining store-insensitive Ca(2+) influx. This store-insensitive calcium sensing component was blocked by the PLC antagonist U73122. Also, the calcium channel inhibitor SKF 96365, a blocker of store-independent trp-like channels, was effective in inhibiting calcium sensing in the presence of thapsigargin. Thus, a store-independent component of calcium sensing was associated with ion channels linked to PLC. Since receptor activated transient receptor potential (trp) family cation channels open in a PLC-dependent and store-independent manner, we suggest that receptor operated channels are activated in osteoclasts stimulated by high extracellular Ca(2+).

ADP-ribosyl Cyclase↗
PubMed2005

Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels.

The melastatin-related transient receptor potential channel TRPM2 is a plasma membrane Ca2+-permeable cation channel that is activated by intracellular adenosine diphosphoribose (ADPR) binding to the channel's enzymatic Nudix domain. Channel activity is also seen with nicotinamide dinucleotide (NAD+) and hydrogen peroxide (H2O2), but their mechanisms of action remain unknown. Here, we identify cyclic adenosine diphosphoribose (cADPR) as an agonist of TRPM2 with dual activity: at concentrations above 100 microM, cADPR can gate the channel by itself, whereas lower concentrations of 10 microM have a potentiating effect that enables ADPR to gate the channel at nanomolar concentrations. ADPR's breakdown product adenosine monophosphate (AMP) specifically inhibits ADPR, but not cADPR-mediated gating of TRPM2, whereas the cADPR antagonist 8-Br-cADPR exhibits the reverse block specificity. Our results establish TRPM2 as a coincidence detector for ADPR and cADPR signaling and provide a functional context for cADPR as a second messenger for Ca2+ influx.

Adenosine Monophosphate↗
PubMed2000

Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5.

Mammalian transient receptor potential channels (TRPCs) form a family of Ca(2+)-permeable cation channels currently consisting of seven members, TRPC1-TRPC7. These channels have been proposed to be molecular correlates for capacitative Ca(2+) entry channels. There are only a few studies on the regulation and properties of the subfamily consisting of TRPC4 and TRPC5, and there are contradictory reports concerning the possible role of intracellular Ca(2+) store depletion in channel activation. We therefore investigated the regulatory and biophysical properties of murine TRPC4 and TRPC5 (mTRPC4/5) heterologously expressed in human embryonic kidney cells. Activation of G(q/11)-coupled receptors or receptor tyrosine kinases induced Mn(2+) entry in fura-2-loaded mTRPC4/5-expressing cells. Accordingly, in whole-cell recordings, stimulation of G(q/11)-coupled receptors evoked large, nonselective cation currents, an effect mimicked by infusion of guanosine 5'-3-O-(thio)triphosphate (GTPgammaS). However, depletion of intracellular Ca(2+) stores failed to activate mTRPC4/5. In inside-out patches, single channels with conductances of 42 and 66 picosiemens at -60 mV for mTRPC4 and mTRPC5, respectively, were stimulated by GTPgammaS in a membrane-confined manner. Thus, mTRPC4 and mTRPC5 form nonselective cation channels that integrate signaling pathways from G-protein-coupled receptors and receptor tyrosine kinases independently of store depletion. Furthermore, the biophysical properties of mTRPC4/5 are inconsistent with those of I(CRAC), the most extensively characterized store-operated current.

Animals↗
PubMed2004

An alternative splicing product of the murine trpv1 gene dominant negatively modulates the activity of TRPV1 channels.

Transient receptor potential vanilloid 1 (TRPV1), or vanilloid receptor 1, is the founding member of the vanilloid type of TRP superfamily of nonselective cation channels. TRPV1 is activated by noxious heat, acid, and alkaloid irritants as well as several endogenous ligands and is sensitized by inflammatory factors, thereby serving important functions in detecting noxious stimuli in the sensory system and pathological states in different parts of the body. Whereas numerous studies have been carried out using the rat and human TRPV1 cDNA, the mouse TRPV1 cDNA has not been characterized. Here, we report molecular cloning of two TRPV1 cDNA variants from dorsal root ganglia of C57BL/6 mice. The deduced proteins are designated TRPV1alpha and TRPV1beta and contain 839 and 829 amino acids, respectively. TRPV1beta arises from an alternative intron recognition signal within exon 7 of the trpv1 gene. We found a predominant expression of TRPV1alpha in many tissues and significant expression of TRPV1beta in dorsal root ganglia, skin, stomach, and tongue. When expressed in HEK 293 cells or Xenopus oocytes, TRPV1alpha formed a Ca(2+)-permeable channel activated by ligands known to stimulate TRPV1. TRPV1beta was not functional by itself but its co-expression inhibited the function of TRPV1alpha. Furthermore, although both isoforms were synthesized at a similar rate, less TRPV1beta than TRPV1alpha protein was found in cells and on the cell surface, indicating that the beta isoform is highly unstable. Our data suggest that TRPV1beta is a naturally occurring dominant-negative regulator of the responses of sensory neurons to noxious stimuli.

Alternative Splicing↗
PubMed2002

Receptor-operated Ca2+ influx channels in leukocytes: a therapeutic target?

Receptor-mediated activation of leukocytes by inflammatory stimuli elicits Ca2+ ion influx as a common and important activation mechanism that has been well established in the literature for over a decade. Inhibiting such receptor-operated Ca2+ influx channels is a potentially attractive strategy for developing anti-inflammatory drugs to attenuate leukocyte activation. Until very recently, the molecular identity of these channels has been unknown, which has hampered drug development in this area. However, the recent explosion of molecular information about one particular family of non-voltage-activated Ca2+ channels, the transient receptor potential (TRP) channels, together with emerging knowledge of their distribution, function and regulation, suggests that they represent a key subgroup of these channels and are therefore potentially attractive drug targets.

Animals↗
PubMed2005

TRPC1 forms the stretch-activated cation channel in vertebrate cells.

The mechanosensitive cation channel (MscCa) transduces membrane stretch into cation (Na(+), K(+), Ca(2+) and Mg(2+)) flux across the cell membrane, and is implicated in cell-volume regulation, cell locomotion, muscle dystrophy and cardiac arrhythmias. However, the membrane protein(s) that form the MscCa in vertebrates remain unknown. Here, we use an identification strategy that is based on detergent solubilization of frog oocyte membrane proteins, followed by liposome reconstitution and evaluation by patch-clamp. The oocyte was chosen because it expresses the prototypical MscCa (>or=10(7)MscCa/oocyte) that is preserved in cytoskeleton-deficient membrane vesicles. We identified a membrane-protein fraction that reconstituted high MscCa activity and showed an abundance of a protein that had a relative molecular mass of 80,000 (M(r) 80K). This protein was identified, by immunological techniques, as the canonical transient receptor potential channel 1 (TRPC1). Heterologous expression of the human TRPC1 resulted in a >1,000% increase in MscCa patch density, whereas injection of a TRPC1-specific antisense RNA abolished endogenous MscCa activity. Transfection of human TRPC1 into CHO-K1 cells also significantly increased MscCa expression. These observations indicate that TRPC1 is a component of the vertebrate MscCa, which is gated by tension developed in the lipid bilayer, as is the case in various prokaryotic mechanosensitive (Ms) channels.

Animals↗
PubMed2005

TRPC1: store-operated channel and more.

Transient receptor potential canonical 1 (TRPC1) is a transmembrane protein expressed in a range of vertebrate cells including smooth muscle, endothelium, neurones and salivary gland cells. It functions as an element of a mixed cationic Ca(2+)-permeable channel, probably commonly as part of a heterotetrameric assembly involving other related proteins such as TRPC5. Wide-ranging biological roles of TRPC1 are suggested, including regulation of smooth muscle and stem cell proliferation, endothelin-evoked arterial contraction, salivary gland secretion, endothelial permeability, glutamatergic neurotransmission, growth cone turning, neuroprotection, neuronal differentiation, lipid raft integrity and the nuclear factor of activated T-cell transcription factor. The mechanisms by which TRPC1 serves these functions are starting to emerge. At one level, it is apparent that TRPC1 is subcellularly compartmentalised, at least in part in cholesterol-rich caveolae closely associated with sub-plasmalemmal endoplasmic reticulum. At another level, TRPC1 is embedded in a protein complex that can include inositol trisphosphate receptor, homer, calmodulin, caveolin-1, FKBP25, I-mfa, MxA, GluR1alpha, bFGFR-1, G(q/11) protein, phospholipase C-beta/gamma, protein kinase C-alpha and RhoA. It is also apparent that TRPC1 responds to general stimuli-not only depletion of intracellular Ca(2+) stores, but also receptor activation, and membrane stretch. We are at the early stages of understanding of how these various signals and components integrate to form a functional channel, and this article provides a brief overview of current progress.

Amino Acid Sequence↗
PubMed2002

Involvement of TRPC in the abnormal calcium influx observed in dystrophic (mdx) mouse skeletal muscle fibers.

Duchenne muscular dystrophy results from the lack of dystrophin, a cytoskeletal protein associated with the inner surface membrane, in skeletal muscle. The absence of dystrophin induces an abnormal increase of sarcolemmal calcium influx through cationic channels in adult skeletal muscle fibers from dystrophic (mdx) mice. We observed that the activity of these channels was increased after depletion of the stores of calcium with thapsigargin or caffeine. By analogy with the situation observed in nonexcitable cells, we therefore hypothesized that these store-operated channels could belong to the transient receptor potential channel (TRPC) family. We measured the expression of TRPC isoforms in normal and mdx adult skeletal muscles fibers, and among the seven known isoforms, five were detected (TRPC1, 2, 3, 4, and 6) by RT-PCR. Western blot analysis and immunocytochemistry of normal and mdx muscle fibers demonstrated the localization of TRPC1, 4, and 6 proteins at the plasma membrane. Therefore, an antisense strategy was used to repress these TRPC isoforms. In parallel with the repression of the TRPCs, we observed that the occurrence of calcium leak channels was decreased to one tenth of its control value (patch-clamp technique), showing the involvement of TRPC in the abnormal calcium influx observed in dystrophic fibers.

Animals↗
PubMed2002

Calcium release and influx in yeast: TRPC and VGCC rule another kingdom.

Calcium is one of the most ubiquitous second messengers, in addition to being a fundamentally important cofactor for many proteins' functions. Thus, cells from fungi to plants to animals have evolved mechanisms for carefully controlling calcium concentrations in their organelles and cytosol. This perspective discusses the similarities and differences between yeast and animals in cation channels of two families: the transient receptor potential channels (TRPCs) and voltage-gated calcium channels (VGCCs). One of the key differences highlighted is in the channels implicated in the response of yeast and animal cells to depletion of calcium from intracellular stores, and the differences in localization of these channels between yeast and animal cells. Understanding the logic of fungal Ca(2+) channels, therefore, may provide new insights into the organization and regulation of cellular calcium signaling networks in animals.

Animals↗
PubMed2003

Mechanosensitive cation channels in arterial smooth muscle cells are activated by diacylglycerol and inhibited by phospholipase C inhibitor.

Mechanosensitive cation channels may be involved in the development of the myogenic tone of arteries. The molecular identity of these channels is not clear, but transient receptor potential channels (TRPCs) are good candidates. In the present study, we searched for mechanosensitive channels at the single-channel level in arterial smooth muscle cells using the patch-clamp technique and investigated the channel properties in the light of properties of TRPCs. With 140 mmol/L CsCl in the pipette solution, application of negative pressures to the back of the pipette induced the activation of channels the open probability of which increased with the amount of negative pressure. The current-voltage relationship was linear in symmetrical ionic conditions, and the single-channel conductances for Cs+, K+, and Na+ were 30, 36, and 27 pS, respectively. When NMDG+ was substituted for Cs+ in the pipette solution, inward currents were abolished, whereas outward currents remained active, indicating that the channels were nonselective to cations. The channel activity was blocked by intracellular Gd3+ and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid and increased by diacylglycerol and by cyclopiazonic acid. Phospholipase C inhibitor (U73122) inhibited not only channel activity but also the development of myogenic tone induced by stretching of the basilar arteries. These results suggest that the ion channel responsible for the development of myogenic tone is the 30-pS mechanosensitive cation channel that exhibits properties similar to those of TRPCs.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2006

Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells.

Oxygen causes perinatal pulmonary dilatation. Although fetal pulmonary artery smooth muscle cells (PA SMC) normally respond to an acute increase in oxygen (O2) tension with a decrease in cytosolic calcium ([Ca2+]i), an acute increase in O2 tension has no net effect on [Ca(2+)](i) in PA SMC derived from lambs with chronic intrauterine pulmonary hypertension (PHTN). The present experimental series tests the hypothesis that an acute increase in O2 tension decreases capacitative calcium entry (CCE) in normal, but not hypertensive, fetal PA SMC. PA SMC were isolated from late-gestation fetal lambs after either ligation of the ductus arteriosus (PHTN) or sham (control) operation at 127 days gestation. PA SMC were isolated from the distal PA (>or=4th generation) and maintained under hypoxic conditions ( approximately 25 Torr) in primary culture. After fura 2 loading, apparent [Ca2+]i in PA SMC was determined as the ratio of 340- to 380-nm fluorescence intensity. Under both hypoxic and normoxic conditions, cyclopiazonic acid (CPA) increased [Ca2+]i more in PHTN than in control PA SMC. CCE was determined in PA SMC under hypoxic and normoxic conditions, after superfusion with zero extracellular Ca2+ and intracellular store depletion with CPA, followed by superfusion with Ca2+-containing solution, in the presence of the voltage-operated calcium channel blockade. CCE was increased in PHTN compared with control PA SMC under conditions of both acute and sustained normoxia. Transient receptor potential channel gene expression was greater in control compared with PHTN PA SMC. PHTN may compromise perinatal pulmonary vasodilation, in part, by modulating PA SMC CCE.

Animals↗
PubMed2005

Mutually exclusive glomerular innervation by two distinct types of olfactory sensory neurons revealed in transgenic zebrafish.

The olfactory epithelium of fish contains two major types of olfactory sensory neurons (OSNs) that are distinct morphologically (ciliated vs microvillous) and possibly functionally. Here, we found that these OSNs express different sets of signal transduction machineries: the ciliated OSNs express OR-type odorant receptors, cyclic nucleotide-gated channel A2 subunit, and olfactory marker protein (OMP), whereas the microvillous OSNs express V2R-type receptors and transient receptor potential channel C2 (TRPC2). To visualize patterns of axonal projection from the two types of OSNs to the olfactory bulb (OB), we generated transgenic zebrafish in which spectrally distinct fluorescent proteins are expressed in the ciliated and microvillous OSNs under the control of OMP and TRPC2 gene promoters, respectively. An observation of whole-mount OB in adult double-transgenic zebrafish revealed that the ciliated OSNs project axons mostly to the dorsal and medial regions of the OB, whereas the microvillous OSNs project axons to the lateral region of the OB. A careful histological examination of OB sections clarified that the axons from the two distinct types of OSNs target different glomeruli in a mutually exclusive manner. This segregation is already established at very early developmental stages in zebrafish embryos. These findings clearly demonstrate the relationships among cell morphology, molecular signatures, and axonal terminations of the two distinct types of OSNs and suggest that the two segregated neural pathways are responsible for coding and processing of different types of odor information in the zebrafish olfactory system.

Animals↗
PubMed2003

The mouse C-type transient receptor potential 2 (TRPC2) channel: alternative splicing and calmodulin binding to its N terminus.

Channels of the C-type transient receptor potential (TRPC) are involved in agonist-stimulated and capacitative calcium entry. There are seven TRPCs, all of which have a Ca(2+)-dependent calmodulin (CaM)-binding domain in their C termini. We now tested binding of CaM to TRPC N termini and show that only that of TRPC2 binds CaM in a Ca(2+)-dependent manner. Four TRPC2 cDNAs have been reported: a (also clone 14), b (also clone 17), alpha, and beta. Sequences responsible for CaM binding in TRPC2 a and b are absent from the alpha and beta isoforms. The alpha and beta cDNAs of TRPC2 were reported as alternative forms, when recloning of TRPC2 a and b proved impossible. Here we analyzed total RNA samples from brain and testis for presence of TRPC2 a and b and describe the splicing patterns responsible for their formation, as well as those leading to the alpha and beta forms of TRPC2. We re-assert existence of RNA encoding the TRPC2 a and b, encoded in 21 exons with an initiator ATG in exon 2 for TRPC2a and in exon 4 for TRCP2b. The analysis of alpha and beta TRPC2 cDNAs indicates that although the TRPC2 beta mRNA may exist, the TRPC2 alpha cDNA is derived from an incompletely processed TRPC2a mRNA: It includes in its presumed 5'-untranslated sequence, 713 nt of TRPC2a cDNA fused to 291 nt of an incompletely excised intron. While encoding an active channel in the mouse, the human TRPC2 appears to be a pseudogene. We searched for the human gene in the data bank and located approximately one-half of it in a chromosomal region syntenic to that of the mouse, with similar intron-exon structure. We conclude that the human TRPC2 gene may never have been an active gene because of incomplete ancestral duplication or, if it was complete at one point, that it became inactive upon loss of chromosomal sequences.

Alternative Splicing↗